Cross-talk between circRNAs and m6A modifications in solid tumors

Circular RNAs (circRNAs) possess unique biological properties and distribution characteristics that enable a variety of biological functions. N6-methyladenosine (m6A), a prevalent epigenetic modification in organisms, is regulated by factors including methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). These factors play critical roles in various pathophysiological processes. There is growing evidence that m6A modifications are common within circRNAs, affecting their synthesis, translation, translocation, degradation, and stability. Additionally, circRNAs regulate biological processes that influence m6A modifications. This review explores the metabolism and functions of m6A modifications and circRNAs, their interactions, and their specific regulatory mechanisms in different tumors, offering insights into m6A-circRNA interaction in cancer.


Introduction
Circular RNAs (circRNAs) were identified within the genomes of viruses and the cytoplasm of eukaryotic cells as far back as the 1970s.Initially, they were dismissed as "junk" resulting from aberrant splicing events due to the limited understanding of that era [1][2][3].Recent advancements in high-throughput RNA sequencing and bioinformatics have consistently demonstrated the existence of circRNAs across a wide range of organisms, including plants [4], parasites [5], and most mammals [6].These circRNAs exhibit distinctive biological properties and distribution patterns, playing critical roles in regulating normal physiological functions and contributing to the development of various diseases [7].review discusses the biological metabolism and functions of circRNAs and m6A regulators, the interactions between circRNAs and m6A modifications, and the specific mechanisms of their interaction in different types of tumors.Additionally, it examines the potential and challenges of leveraging the interaction between circRNAs and m6A modifications in cancer therapy, based on current research findings.

CircRNAs and M6A modifications
CircRNAs circRNAs, characterized by their covalently closed loop structure without a 5′ cap and 3′ tail, are mainly synthesized through introns pairing [15], RNA binding proteins (RBPs) pairing [16], lariat formation [17] and other mechanisms.They are not only resistant to degradation by exonucleases such as exonucleases [18], but also form unique cell-and tissue-specific RNA loops via selective splicing [19].CircRNAs can be categorized based on their splicing sequences into exonic circRNAs (Ecir-cRNAs), exon-intron circRNAs (EIciRNAs), intronic cir-cRNAs (CiRNAs), and others, such as tricRNAs which result from tRNA splicing and whose function is not yet clear [20][21][22].Although primarily produced in the nucleus, circRNAs can move to the cytoplasm through various mechanisms [23].For example, m6A-modified circNSUN2 can be exported from the nucleus to the cytoplasm by YTHDC1 in colorectal cancer, and circRNAs may undergo degradation by RNase L [24], miRNAs [25], and YTHDF2 [26], etc., under certain conditions.In addition, circRNAs in the nucleus possess the capability to regulate transcription and splicing of their parental genes through various mechanisms.For instance, Zhang et al. and Li et al. discovered that ciRNAs (ci-ankrd52) and EIciRNAs (circEIF3J/circPAIP2) in the nucleus can interact with Pol II and regulate the transcription of their parent genes [21,27].CircRNAs in the cytoplasm can influence post-transcriptional regulation [17].They may serve as miRNA sponges, competing with miRNAs to bind to miRNA recognition elements on target genes and increasing target gene expression [28].For example, circMETTL3 increase the expression of CDK1 by binding to miR-31-5p, thereby promoting the advancement of breast cancer [29].Alternatively, they can be translated into polypeptides through mechanisms such as recruiting ribosomes in an internal ribosome entry site-dependent manner [30], or recruiting EIF4G2 and YTHDF3 in an m6A modification-dependent manner [31].Additionally, circRNAs can interact with proteins, acting as protein sponges, decoys, scaffolds, or assisting in translocation to regulate the expression levels of themselves or downstream target molecules [18].For example, circFoxo3 serves as a scaffold to mediate the combination of CDK2 and p21 to form a ternary complex, thereby blocking the cell cycle progression and keeping it in G1 phase [32] (Fig. 1).

Interaction of m6A modifications with circRNAs
m6A modifications can act on circRNAs, influencing their metabolism and functions including biosynthesis, cellular distribution, translation, and degradation.Conversely, circRNAs can also affect the m6A modification process, underscoring a complex interaction between the two, as depicted in Fig. 2.

M6A modifications regulate circRNAs
m6A modifications regulate the synthesis, degradation, translation, and cellular distribution of circRNAs, and affect tumorigenesis, progression and therapeutic resistance [59].Changes in m6A modification levels can alter circRNA synthesis levels.Tang et al. observed that cir-cRNA with increased levels in haploid male germ cells during spermatogenesis contains m6A modifications, which can be influenced by ALKBH5 and METTL3 [60].Dattilo et al. found that YTHDC1 can cooperate with RNA helicase DDX5 to promote the synthesis of m6Amodified circRNAs in rhabdomyosarcoma (RMS), which control the proliferation activity of RMS cells [61].Additionally, circRNAs can also be subjected to degradation by m6A modifications.For example, m6A-modified cir-cRNAs can be cleaved by RNase P/MRP endoribonuclease in an HRSP12-dependent manner in the presence of YTHDF [26].M6A-modified circMPP1 can be degraded in the presence of YTHDC1, which can be involved in regulating trophoblast function in the placental tissue [62].CircRNAs, previously thought to lack translational capacity due to the absence of a 5′ translation initiation cap structure, have been found to be translatable in the presence of m6A.Yang et al. noted that m6A-modified circRNAs in human cells could initiate translation through EIF4G2 and the m6A reader YTHDF3 [31].Duan et al. and Zhong et al. found that IGF2BP1 and YTHDF2 could bind specifically to circMAP3K4 and circMET, respectively, mediating their translation in a cap-independent manner, thereby contributing to the regulation of tumor progression [63,64].M6A modifications also play a role in the translocation of circRNAs, with Chen et al. showing that YTHDC1 can mediate the translocation of circNSUN2 from the nucleus to the cytoplasm by binding to its m6A modification site in colorectal cancer (CRC) [65].Other researchers also found that IGF2BP2 and HNRNPC can mediate the transport of circCDK1 and circZBTB44 into the cytoplasm in laryngeal squamous cell carcinoma and renal cell carcinomas, respectively [66,67].

CircRNAs regulate m6A modifications
In addition to the relationships mentioned above, cir-cRNAs also regulate the transport, degradation, and post-transcriptional levels of m6A regulators, and participate in tumor genesis, therapeutic resistance, metabolism and metastasis.CircRNAs can mediate the export of m6A regulators to the cytoplasm.Huang et al. found that circSTAG1, which is down-regulated in the the chronic unpredictable stress-treated mouse hippocampus and in peripheral blood of patients with major depressive disorder (MDD), can promote its translocation to the nucleus through decreased binding to ALKBH5.This leads to astrocyte dysfunction and depressive-like behavior [68].CircRNAs also play a role in the degradation of m6A regulators.M6A-modified circNDUFB2 binds to IGF2BPs, serving as scaffolds to mediate the interaction between TRIM25 and IGF2BPs, ultimately promoting the ubiquitination and degradation of the IGF2BP and advancing NSCLC progression [69].Similarly, circEZH2 prevents the ubiquitin-dependent degradation of IGF2BP2 by interacting with it and increases IGF2BP2 expression by binding to miR-133b, thereby promoting CRC progression by enhancing the stability of CREB1 mRNA [70].Additionally, as "miRNA sponges, " circRNAs can regulate the post-transcriptional expression of m6A regulators.For instance, circMAP2K4 upregulates YTHDF1 expression by binding to has-miR-139-5p, promoting HCC progression [71].Circ0072083 increases ALKBH5 expression by binding to miR-1252-5p, and reducing m6A modification, improving the stability of NANOG mRNA, and regulating temozolomide resistance in gliomas [72].Circ_0072309 can increase FTO expression by binding to miR-607, which ultimately promotes NSCLC progression [73].CircBACH2 increases HNRNPC expression by binding to hasmiR-944, which subsequently activates MAPK signaling pathway to promote the proliferation of breast cancer cells [74].Finally, circRNAs can regulate the expression of m6A-modified mRNAs by interacting with m6A regulators.For example, circXPO1 can improve the stability of CTNNB1 mRNA by interacting with IGF2BP1, thus promoting the progression of LUAD [75].CircUHRF2 can promote the interaction between IGF2BP1 and DDX27 mRNA by recruiting IGF2BP1, which inhibits the loss of DDX27 protein, and promotes the occurrence and metastasis of CRC [76].

Crosstalk between M6A modifications and CircRNAs in solid tumors
Advanced research techniques have highlighted the role of circRNAs and m6A modifications in processes such as human cancer development.This review summarizes the crosstalk between circRNAs and m6A modifications across various tumors (Table 2 and 3).

Glioma
m6A-modified circRNAs can function as competing endogenous RNAs (ceRNAs) in glioma tumorigenesis and proliferation.For instance, circDLC1 and circ_103239 increase their stability through m6A modification through m6A writers.Subsequently, circDLC1 promotes CTNNBIP1 transcription in vivo by competitively binding miR-671-5p, which inhibits glioma cells' malignant proliferation [77].Similarly, circ_103239 boosts MTSS1 expression by binding miR-182-5p, thereby inhibiting epithelial-to-mesenchymal transition (EMT) in glioma [78].m6A-modified circRNAs also influence glioma progression through their translational effects.For example, m6A-modified circMET can be translated into MET404 in response to YTHDF2, activating MET receptors in the HGF/MET signaling pathway in glioma by interacting with the MET β-subunit.Consequently, combining MET404 antibodies with conventional MET inhibitors could offer a new therapeutic approach for GBM patients with MET hyperactivation [63].
CircRNAs play a critical role in regulating m6A modifiers in glioma tumorigenesis and drug resistance.Circ-NEIL3 interacts with IGF2BP3, protecting it from ubiquitination and degradation by E3 ubiquitin ligase-HECTD4.This activation of the YAP1 signalling pathway encourages macrophage infiltration into the tumor microenvironment in glioma cells, contributing to glioma progression [79].Circ_0072083 and circTTLL13 specifically combat temozolomide resistance in gliomas.Mechanistically, circ_0072083 elevates ALKBH5 expression by binding to miR-1252-5p, which lessens m6A modification of NANOG mRNA and boosts its stability [72].CircTTLL13 mediates the m6A modification of OLR1 pre-mRNA by recruiting METTL3 in the nucleus, enhancing m6A-modified OLR1 mRNA stability in the Fig. 2 The crosstalk between m6A and circRNAs.m6A modifications affect the processes of biogenesis, translocation, translation, and degradation of circRNAs, which affect the post-transcriptional levels, translocation, and degradation of m6A regulators, as well as changes in the levels of m6A mRNAs   [66].

Non-small cell lung cancer
Recent findings reveal that circIGF2BP3 binds YTHDC1 through METTL3-mediated m6A modification, enhancing its synthesis.It also mitigates its suppressive effect on PKP3 by sequestering miR-328-3p and miR-3173-5p, subsequently increasing the stability of OTUB1 mRNA.This process allows PKP3 to interact with FXR1, safeguarding PD-L1 from proteasome-mediated degradation, thereby fostering immunosuppression and immune escape in non-small cell lung cancer (NSCLC) [85].Conversely, m6A-modified circFUT8, regulated by YTHDF2 can not only competitively interacte with YTHDF2 and blunt its binding to mFUT8, but also bind to miR-186-5p to enhance the stability of mFUT8, thereby promoting the malignancy in lung adenocarcinoma (LUAD) [86].Moreover, m6A-modified circASK1, which is reduced in gefitinib-resistant LUAD due to YTHDF2-mediated degradation, can rescue the pro-apoptotic activity of ASK1/  Anti-oncogene [149] Table 3 circRNAs affect m6A modification JNK/p38 signaling pathway through the interaction of its encoded protein ASK1-272a.awith Akt, thereby inducing apoptosis of LUAD cells and increasing gefitinib sensitivity [87].CircKRT17, which gains stability through METTL3-mediated m6A modification in osimertinibresistant LUAD, aids in the nuclear translocation and stabilization of YAP1 by recruiting EIF4A3.This action contributes to osimertinib resistance in LUAD [88].
CircRNAs are also implicated in lung cancer tumorigenesis and therapeutic resistance by influencing m6A regulators.Some circRNAs act by binding to microR-NAs (miRNAs).For instance, circ_0072309 can upregulate FTO by binding to miR-607 [73].CircVMP1 boosts METTL3 expression, leads to m6A modification of SOX2 mRNA, and enhances SOX2 mRNA stability by binding to miR-524-5p [89], which, in turn, promotes NSCLC cell proliferation and invasion.Other circRNAs function by being translated into peptides.For example, circFBXW7 engages with β-catenin in an m6A-dependent manner through its peptide circFBXW7-185, prompting the ubiquitination and degradation of β-catenin.This inhibits the activation of the classical Wnt signaling pathway, reduces Let-7d expression inhibition, lowers YTHDF3 levels, and curbs circFBXW7 translation, creating a feedback loop that regulates the properties and therapeutic resistance of LUAD stem cells [90].Additionally, some circRNAs regulate downstream mRNAs.For instance, circXPO1 enhances LUAD progression by interacting with IGF2BP1 and increasing the stability of CTNNB1 mRNA [75].CircNOTCH1 enhances NSCLC progression by competitively interacting with METTL14 and NOTCH1 mRNA, reducing the m6A modification level of NOTCH1 mRNA, thereby maintaining its stability [91].Similarly, circEML4, through the delivery of M2-polarized macrophage extracellular vesicles induced by cigarette smoke extract, facilitates ALKBH5's translocation to the cytoplasm in NSCLC cells.This action increases the m6A modification of SOCS2, lowers SOCS2 expression, stimulates the JAK-STAT pathway, and promotes NSCLC progression [92].

Colorectal cancer
M6A modifications play a critical role in the degradation of circRNAs in colorectal cancer (CRC).The m6Amodified circ3823, for instance, can be degraded by the YTHDF3/ALKBH5/YTHDF2 mechanism.However, circ3823 also influences the expression of TCF7 and its downstream molecules, MYC and CCND1, by binding to miR-30c-5p, which then activates the Wnt signalling pathway, fostering CRC progression [111].Similarly, m6A-modified circAFF2 and circ_0003215 can also be degraded by YTHDF2, while circAFF2 inhibits the neddylation modification of CRC cells and enhances the radiosensitivity of CRC by facilitating the interaction of CAND1 with Cullin 1 [112].The m6A-modified circ_0003215 elevates DLG4 expression by binding to miR-663b, promoting the k48-linked G6PD ubiquitination and inhibiting pentose phosphate metabolism in CRC cells, thereby inhibiting CRC progression [113].Moreover, m6A modifications can mediate the cytoplasmic translocation of circRNAs.For instance, Fig. 4 circRNAs regulate m6A modifications in hepatocellular carcinoma (HCC).CircRNAs mainly regulate the post-transcriptional levels of m6A regulators by binding to miRNAs in HCC.And regulate the expression of m6A mRNAs by interacting with m6A regulators in HCC m6A-modified circNSUN2 can move to the cytoplasm under the influence of YTHDC1 and may promote liver metastasis in CRC by enhancing HMGA2 mRNA stability through the circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex [65].Another example is m6A-modified circFNDC3B, which, influenced by YTHDC1, can inhibit CRC progression and metastasis by binding to FXR2, maintaining RNF41 stabilization, and promoting the ubiquitination and degradation of ASB6 [114].m6A modifications play a pivotal role in the translation of circRNAs.An example of this is m6A-modified circYAP, which is translated into YAP protein, YAP-220aa under the action of YTHDF3 and EIF4G2.Subsequently, YAP-220aa facilitates the nuclear translocation of YAP by interacting with LATS1.These mechanisms promote CRC invasiveness and liver metastasis [115].Moreover, several circRNAs exhibiting increased stability and upregulated expression due to m6A modifications in CRC have been identified.These circRNAs include circ1662 that inhibits CRC epithelial mesenchymal transition (EMT) by binding to YAP1 protein, promoting its translocation to the nucleus and down-regulating SMAD3 expression [116]; circALG1 that promotes the metastasis of CRC by increasing PGF expression through binding to miR-342-5p [117]; circ_0000677 that facilitates CRC progression by increasing ABCC1 expression through binding to miR-655 [118]; circQSOX1 that promotes Treg cell-mediated CRC immune escape by increasing PGAM1 expression through binding to miR-326 and miR-330-5p [119]; and circ_0124554 that promotes CRC progression and radiotherapy resistance by increasing LASP1 expression through binding miR-1184 [120].
Additionally, numerous studies have highlighted how circRNAs regulate m6A regulators, with some blocking the action of miRNAs.For instance, circPTK2 can elevate YTHDF1 expression by binding to miR-136-5p, potentially enhancing CRC progression and chemoresistance by activating the Wnt/β-catenin signaling pathway [121].CircEZH2 not only interacts with IGF2BP2, preventing its ubiquitin-dependent degradation, but also increases IGF2BP2 expression by binding to miR-133b, which enhances CREB1 mRNA stability and promotes CRC progression [70].Some circRNAs can affect the expression of downstream target mRNAs through interactions with m6A regulators.For example, circMYH9 can recruit HNRNPB2A1 in the nucleus.This recruitment inhibits HNRNPB2A1's binding to the m6A-modified p53 pre-mRNA, diminishing p53's inhibitory effect on PHGDH expression, promoting serine-glycine metabolism and redox homeostasis, and ultimately facilitating CRC progression [122].CircUHRF2, with expression upregulated by m6A modification in response to METTL3, enhances its interaction with DDX27 mRNA by recruiting IGF2BP1, promoting CRC occurrence and metastasis [76].CircASPH enhances the stability of m6A-modified STING mRNA by binding and stabilizing the IGF2BP2 protein, which, in turn, promotes M2 macrophage polarization and accelerates CRC progression through exosome-mediated STING transfer to macrophages [123].

Gynecological cancer
In breast cancer, Li et al. discovered that circMETTL3, with upregulated expression due to METTL3-induced m6A modification, could bind miR-31-5p and increase CDK1 expression, promoting breast cancer cels proliferation and metastasis [29].By contrast, Ruan et al. found that circMETTL3 could boost METTL3 expression by binding to miR-34c-3p, hence suppressing triplenegative breast cancer cells proliferation and metastasis [124].Additionally, Lv et al. found that circBACH2, with upregulated expression in breast cancer, could increase the expression of HNRNPC by binding to has-miR-944, activating the MAPK signaling pathway, and promoting breast cancer cells proliferation [74].
In endometrial cancer (EC), Zhang et al. found that circNAB1, which is upregulated by ALKBH5 in an m6A-YTHDF2-dependent manner, can enhance CDKN3 expression by binding to miR-876-3p, thus promoting the proliferation and progression of EC [125].Similarly, Shi et al. discovered that circCHD7 enhances the stability of PDGFRB mRNA in an m6A-dependent manner by interacting with IGF2BP2, thereby activating the JAK/STAT signaling pathway and promoting the proliferation of EC cells [126].
In cervical cancer, Persistent infection with human papillomavirus (HPV) is a significant risk factor for cervical cancer progression [127].Zhao et al. demonstrated that circE7, formed after HPV infection, can produce the E7 oncoprotein through its own m6A modification, contributing to cervical cancer cell growth [128].Chen et al. discovered that circ_0000069, with increased stability due to m6A modification, promotes cervical cancer cell proliferation and metastasis by interacting with miR-4426 [129].Further studies by Liang et al. and Shi et al. identified circCCDC134 and circRNF13, which express m6A modifications and are regulated by YTHDF2 in cervical cancer [130,131].Ji et al. found that circARH-GAP12, with elevated m6A modification levels, can bind to m6A-modified FOXM1 mRNA through IGF2BP2.This binding leads to the formation of a circARHGAP12/ IGF2BP2/FOXM1 triplex complex, enhancing FOXM1 mRNA stability and promoting cervical cancer cell proliferation and metastasis [132].
In ovarian cancer, circASXL1, stabilized by m6A modifications through METTL3 and IGF2BP1, increases RACGAP1 expression by binding to miR-320d.This activation of the PI3K/Akt pathway encourages the proliferation and metastasis of ovarian cancer [133].The m6A-modified circNFIX, by binding to IGF2BPs, enhances IL-6R expression through miR-647 interaction.This activation of the JAK1/STAT3 pathway increases PD-L1 expression and stability, facilitating ovarian cancer cell proliferation and immune escape [134].Li et al. discovered that circPLPP4, with increased stability from m6A modification, can induce cisplatin resistance in ovarian cancer by binding to miR-136 and upregulating PIK3R1 [135].Additionally, circRAB11FIP1, upregulated in ovarian cancer, promotes autophagy and malignant progression by enhancing ATG5 and ATG7 mRNA modification through direct interaction with FTO mRNA and an increase in its expression, thereby promoting the malignant progression of epithelial ovarian cancer (EOC) [136].

Urinary tumors
In renal cell carcinoma (RCC), circPOLR2A, regulated by YTHDF2 through m6A modification, enhances the interaction between PEBP1 and UBE3C.This interaction leads to the ubiquitination and degradation of PEBP1 by UBE3C, activating the ERK signaling pathway and promoting the progression and metastasis of clear cell renal cell carcinoma (ccRCC) [137].The m6A-modified circMET, upregulated by NONO-TFE3 fusion proteins, interacts with CDKN2A mRNA in the cytoplasm, promoting its degradation and facilitating NONO-TFE3 tRCC progression [138].Similarly, in RCC, m6A-modified circZBTB44 undergoes translocation into cells in response to HNRNPC to promote interaction with IGF2BP3, which, in turn, enhances macrophage M2 polarization by increasing HK3 expression and, ultimately, promotes immune escape from RCC [67].Cir-cRARS that bind to IGF2BP3 in ccRCC promote ccRCC progression by maintaining the stability of downstream m6A-modified target molecules, such as CAPN15, CD44, HMGA2, TNRC6A, and ZMIZ2 [139].Lastly, upregulated m6A-modified circPPAP2B in ccRCC tissues stabilizes the HNRNPC/Vimentin/Importin α7 complex by binding to HNRNPC, influencing its ubiquitination and degradation.This process promotes the translocation of HNRNPC to the nucleus and facilitates the progression and metastasis of ccRCC [140].
In bladder cancer (BC), circSLC38A1, which is overexpressed due to m6A modification in BC cells, transcriptionally regulates TGF-β2 expression.This regulation occurs through the stabilization and increased expression of the ILF3 protein, thus facilitating BC progression and metastasis [141].Similarly, m6A-modified circPSMA7 in BC cells, stabilized by IGF2BP3, upregulates MAPK1 mRNA expression by binding miR-128-3p, enhancing BC proliferation and metastasis [142].Furthermore, circPT-PRA binds competitively to IGF2BP1 in the cytoplasm, preventing it from recognizing downstream m6A-modified MYC and FSCN1 mRNAs.This action reduces the stability of these mRNAs and inhibits BC progression [143].The increased production of circ_0008399, following the interaction between EIF4A and RBM3 pre-mRNA, interacts with WTAP in the nucleus.This interaction promotes the assembly of m6A methyltransferases (WTAP/METTL3/M3TTL14), leading to the m6A modification of TNFAIP3 mRNAs, which stabilizes them, thereby inhibiting BC cell apoptosis and promoting cisplatin resistance [144].Circ_104797, with its stability enhanced by m6A modification, contributes to cisplatin resistance in BC cells by binding to miR-103a and miR-660-3p [145].
In prostate cancer (PCa), m6A-modified circRBM33 and circFAM126A are significantly upregulated and contribute to cancer proliferation and metastasis both in vivo and in vitro.Specifically, m6A-modified circRBM33, responding to METTL3, forms a binary complex with FMR1 that binds to PDHA1 mRNA.This complex increases PDHA1 mRNA stability and its translational output, enhancing oxidative phosphorylation (ox-pho) in PCa cells and promoting their growth and metastasis [146].The m6A-modified circFAM126A, with increased transcriptional stability due to IGF2BP1 binding, upregulates CANX expression by binding to miR-505-3p.This modulation affects cholesterol synthesis and promotes the malignant progression of prostate cancer [147].Additionally, circDDIT4, with increased synthesis due to m6A methyltransferase complex-mediated modification, acts as an RNA-binding protein sponge.It binds to ELAV1, reducing ANO7 expression and inhibiting PCa progression [148].Moreover, circRNAs can regulate m6A regulators in PCa.For instance, circPDE5A, upregulated by the transcription factor FOXO4 and the RNA-binding protein eIF4A3, binds to WTAP, inhibiting EIF3C mRNA's m6A modification and translation in a YTHDF1dependent manner.This inhibition blocks the MAPK pathway activation, ultimately suppressing PCa progression and metastasis [149].CircABCC4, upregulated by m6A modification in response to METTL3, enhances IGF2BP2 protein stability by promoting its interaction with CCAR1 mRNA.This enhancement activates the Wnt/β-catenin pathway, promoting PCa occurrence and metastasis [150].Lastly, circARHGAP29, whose synthesis and cytoplasmic transport increase following EIF4A3 binding, interacts with IGF2BP2.This interaction stabilizes c-Myc mRNA, subsequently upregulating LDHA mRNA expression and promoting anaerobic glycolysis in PCa cells, which fosters PCa progression and resistance to docetaxel treatment [151].

Other tumors
In esophageal cancer, Wang et al. identified that cir-cRUNX1 expression was markedly increased in esophageal squamous carcinoma (ESCC) tissues.m6A-modified circRUNX1, by binding to IGF2BP2, could enhance its stability, elevate FOXP3 expression through binding to miR-449b-5p, and thus foster ESCC progression [152].
In gastric cancer, Fan et al. discovered that elevated circORC5 levels enhance gastric cancer progression by binding to miR-30c-2-3p and elevating EIF4B and AKT1S1 expression.METTL14 can reduce circORC5 levels through m6A modification, but it is poorly expressed in gastric cancer tissues, correlating with a poor prognosis [153].Additionally, Zhang et al. identified an Epstein-Barr virus (EBV)-encoded circRNA, EBV-cir-cRPMS1, highly expressed in EBV-associated gastric cancer (EBVaGC).It contributes to m6A regulator regulation by recruiting Sam68 to METTL3's promoter region, thereby enhancing METTL3 expression and advancing EBVaGC progression [154].
In melanoma, Zhao et al. identified that circ_0053943, which is overexpressed in uveal melanoma (UM), stabilizes EGFR mRNA in an m6A-dependent manner by binding to IGF2BP3, activating the MAPK/ERK pathway and promoting the proliferation and aggressiveness of UM cells [155].
In rhabdomyosarcoma (RMS), Francesca et al. discovered that there is an upregulated expression of circVAMP3 in a representative cell line of alveolar rhabdomyosarcoma (RH4 cell line), and its m6A modification level is significantly different from its linear counterpart.Therefore, m6A modification may be involved in regulating the selective synthesis between the two.Moreover, circVAMP3 may regulate the cell cycle of RH4 through the AKT pathway and participate in its proliferation [156].Interestingly, Dario et al. described the expression characteristics of circRNA in the context of RMS.Through genome-wide methods, they demonstrated that m6A reader YTHDC1 and RNA helicase DDX5 can jointly mediate the backsplicing of m6A-modified cir-cRNAs in RMS, thereby promoting their synthesis.Then, the regulation of circRNAs expression by the two may be involved in the advancement of RMS [61].
In osteosarcoma, Meng et al. and Liu et al. have discovered that circNRIP1 and circRNF220 can be upregulated by m6A modification due to METTL3 in osteosarcoma cells.CircNRIP1 primarily functions through the miR-199a-FOXC2 pathway, while circRNF220 operates mainly through the miR-330-5p-survivin pathway [157,158].Additionally, Ji et al. found that circKEAP1 is destabilized by m6A modification in OS cells, promoting the ubiquitination and degradation of vimentin through the binding of its encoded protein, KEAP1-259aa, with the E3 ligase ARIH1.This process inhibits the malignant progression of OS cells [159].Similarly, Long et al. and Yang et al. identified circ_0000285 and circCTNNB1 as actors on m6A regulators in OS cells.Circ_0000285 facilitates OS progression by enhancing IGF2BP3 expression through miR-409-3p binding [160].By contrast, circCTNNB1 increases m6A modification of aerobic glycolytic genes, such as GPI, HK2, and PGK1, by binding to RBM15.This action stabilizes and boosts the expression of these target genes, promoting aerobic glycolysis and thus contributing to OS progression [161].

Clinical application and prospects
The crosstalk between circRNAs and m6A modifications mainly affects the tumorigenesis, progression and treatment resistance of solid tumors.Among them, they can affect the above processes by participating in the proliferation, metastasis, metabolism, immunity and autophagy of tumor cells.Therefore, for these mechanisms of action, circRNAs and m6A modification regulators can serve as new tumor therapeutic targets.For example, Du et al. found that significantly upregulated circMDK in HCC is associated with m6A modification and poor survival in HCC patients, and it can enhance the expression of ATG16L1 by binding to miR-346 and miR-874-3, thereby activating the PI3K/AKT/mTOR signaling pathway and promoting the progression of HCC.According to this mechanism, poly (β-amino esters) (PAEs) were synthesized to mediate the delivery of circMDK siRNA (PAE-siRNA) in vivo, thus knocking down circMDK and achieving effective antitumor effects in animal models [99].In addition, circRNAs and m6A modifier regulators may also provide novel strategies for therapeutic resistance of tumors.For example, Li et al.Showed that circFBXW7 effectively inhibits the abilities of LUAD stem cells and reverses resistance to Osimertinib by modulating Wnt pathway functions through the action of circFBXW7-185AA on β-catenin ubiquitination and inhibition.This mechanism provides new ideas and clinical research directions for the effect of circRNAs on TKIs therapeutic resistance in LUAD [90].Finally, circRNAs and m6A modification regulators can also serve as biomarkers for novel tumor diagnosis.For example, Wei et al. reported that circCDYL can be loaded into exosomes under the action of HNRNPA2/B1 to form circCDYLenriched epithelial cell adhesion molecule (EPCAM)positive exosomes, namely liver tumor initiation exosomes (LTi-Exos).It may be combined with plasma alpha-fetoprotein (AFP) as a promising biomarker for early diagnosis of HCC [162].
In addition, according to the current relevant studies, there are still some problems to be solved about the cross-talk between circRNAs and m6A modifications: First, the differential expression of circRNAs and m6A modification regulators in different tumors causes different effects, but the reasons for the differences are still unclear.Second, methylated RNA immunoprecipitation and sequencing (MERIP-seq/ m6A-seq) is currently the main method for detecting m6A modification sites in circRNAs, but its specificity and sensitivity still need to be improved, for example, single nucleotide variation at methylation sites cannot be accurately detected [163].Third, many studies have found that circRNAs and m6A modified regulators can serve as biomarkers for tumor therapy or diagnosis, but at present, it is still not possible to detect specific circRNAs in peripheral blood and achieve precise molecular therapy through siRNAs and other effects.

Conclusions
In this review, we summarize the properties and functions of circRNAs and m6A modifications, and discuss their crosstalk effects in solid tumors.In different cancer types, m6A modification can be involved in regulating the synthesis, translation, transport, degradation and stability of circRNAs.Conversely, circRNAs can also regulate the post-transcriptional level and degradation of m6A modification regulators by binding miRNAs and interacting with m6A modification regulators, or regulate the expression of its downstream m6A-modified target mRNA.Their crosstalk provides a new perspective for the treatment and diagnosis of solid tumors.

Fig. 1
Fig.1The biogenesis and function of circRNAs.CircRNAs can be synthesized in the nucleus by mechanisms such as intron pairing, RNA-binding protein (RBP) pairing, and lariat formation, where they are involved in regulating the transcription and splicing of parental genes, and partially translocated to the cytoplasm through length, m6A, and XPO4-mediated transport, where they are subjected to degradation by RNase L, miRNAs, and YTHDF2, and function by acting as miRNA sponges, translating, and interacting with proteins

Table 1
Types and functions of m6A regulators